A Study of Irinotecan and Cetuximab With or Without IMC-A12 for Treatment of Participants With Colon or Rectum Cancer Who Got Worse After Their First Treatment With Oxaliplatin and Bevacizumab

The purpose of this study is to determine the value of adding IMC-A12 to irinotecan +
cetuximab in improving progression-free survival (PFS) at 18 weeks from the date of
randomization for participants with metastatic Kirsten Rat Sarcoma (K-RAS) wild-type CRC that
has progressed on an oxaliplatin/bevacizumab-containing regimen.

Inclusion Criteria:

- Must consent to be in the study and must have signed and dated Institutional Review
Board (IRB)-approved consent forms conforming to federal and institutional guidelines
for the pre-entry tumor sample submission for central K-RAS testing and for the study
treatment

- Must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or
2

- Must have metastatic CRC

- The CRC tumor or metastatic tumor must be v-Ki-ras2 Kirsten rat sarcoma viral oncogene
homolog gene (K-RAS) wild-type as determined by central testing

- Must be documented disease progression during first-line therapy containing both
oxaliplatin and bevacizumab

- Most recent treatment regimen must have ended ≥21 days prior to randomization, and
clinically significant side effects associated with previous therapy must have
resolved to ≤Grade 1 with the exception of neuropathy which must have resolved to
≤Grade 2

- Imaging of the chest, abdomen and pelvis with computed tomography (CT) scan or
magnetic resonance imaging (MRI) must be performed within 3 weeks prior to
randomization

- Must have measurable disease, defined as at least 1 lesion outside a previous
radiation therapy (RT) field that can be accurately measured in at least 1 dimension
as ≥20 millimeters (mm) with conventional techniques or as ≥10mm with 5mm cuts using a
spiral CT scan

- Evidence of adequate bone marrow function: absolute neutrophil (ANC) ≥1200 cubed
millimeters (mm³), hemoglobin ≥9 grams per deciliter (g/dL), platelets ≥100,000 mm³

- Evidence of adequate hepatic function. If no liver metastases: aspartate
aminotransferase (AST) ≤2.5 times (x) upper limit of normal (ULN), total bilirubin
≤1.5 x ULN for the lab. In the presence of liver metastases: AST ≤5.0 x ULN, total
bilirubin ≤1.5 x ULN for the lab

- Serum creatinine must be ≤1.5 x ULN for the lab

- Must have a fasting blood glucose <126 milligrams/deciliter (mg/dL). Fasting is
defined as no caloric intake for at least 8 hours

Exclusion Criteria:

- Life expectancy less than 12 weeks

- Diagnosis of anal or small bowel carcinoma

- Tumor that is considered by the surgeon to be amenable to complete resection

- Previous RT to >25% of bone marrow

- RT to sites of measurable disease chosen as target lesions

- Radiological evidence and/or clinical signs or symptoms of central nervous system
(CNS) metastases

- Any of the following conditions and events: uncontrolled hypertension, defined as
systolic blood pressure (BP) >150 millimeters of mercury (mmHg) or diastolic BP >100
mmHg with or without antihypertensive medication (participants with hypertension that
is well-controlled on medication are eligible); unstable angina within 6 months before
randomization; New York Heart Association (NYHA) Class III or IV cardiac disease;
myocardial infarction (MI) within 6 months before randomization; symptomatic
arrhythmia; CNS cerebrovascular ischemia [transient ischemic attack (TIA) or stroke]
within 6 months before randomization

- Other malignancies unless the participant is considered to be disease-free and has
completed therapy for the malignancy ≥12 months prior to randomization. Participants
with the following cancers are eligible if diagnosed and treated within the past 12
months: carcinoma in situ of the cervix, colon carcinoma in situ, melanoma in situ,
and basal cell and squamous cell carcinoma of the skin

- Serious or non-healing wound, skin ulcers, or bone fracture

- Any significant bleeding unless the source of bleeding has been resected

- History of bleeding diathesis or coagulopathy (participants on stable anticoagulant
therapy are eligible)

- Any evidence of active infection

- Active inflammatory bowel disease

- Grade 3 or 4 diabetes mellitus as defined by National Cancer Institute's (NCI's)
Common Terminology Criteria for Adverse Events (CTCAE) v 3.0 pancreatic endocrine:
glucose intolerance (participants with diabetes controlled with diet and/or oral
medications are eligible)

- Symptomatic interstitial pneumonitis or definitive evidence of interstitial
pneumonitis described on CT scan or chest x-ray in asymptomatic participants

- Any other serious concomitant medical condition that, in the opinion of the
investigator, would compromise the safety of the participant or compromise the
participant's ability to participate in the study

- Previous hypersensitivity reaction to monoclonal antibodies

- Previous treatment with irinotecan, cetuximab, or any agent specifically targeting
insulin-like growth factor (IGF) receptors

- Treatment with an investigational drug within 30 days prior to randomization

- Pregnancy or lactation at the time of participant entry

- Psychiatric or addictive disorders or other conditions that, in the opinion of the
investigator, would preclude the participant from meeting the study requirements